Isothiocyanate functional surfactant formulation and associated method of use

ABSTRACT

An isothiocyanate functional surfactant formulation, wherein the protonated form of said surfactant is represented by the following chemical structure: 
                         
wherein X includes an integer ranging from approximately 1 to approximately 25, and wherein Y includes an integer ranging from approximately 6 to approximately 25; and an emollient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/594,788, entitled “METHOD FOR TREATING PHYTOPHOTODERMATITIS,” filedJan. 12, 2015, which is a continuation of U.S. application Ser. No.13/342,516, entitled “METHOD FOR TREATING PHYTOPHOTODERMATITIS,” filedJan. 3, 2012, now U.S. Pat. No. 8,933,119, which claims the benefit ofU.S. Provisional Application Ser. No. 61/429,325, entitled “METHOD FORTREATING PHYTOPHOTODERMATITIS,” filed Jan. 3, 2011 and U.S. ProvisionalApplication Ser. No. 61/502,067, entitled “METHOD FOR TREATINGPHYTOPHOTODERMATITIS,” filed Jun. 28, 2011—all of which are herebyincorporated herein by reference in their entirety, including allreferences cited therein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates in general to a method for treatingphytophotodermatitis and, more particularly, to a method for treatingphytophotodermatitis caused by exposure to linear and/or non-linear(e.g., angular) furanocoumarins and derivatives thereof—among otherchemical compounds.

2. Background Art

Phytophotodermatitis (hereinafter sometimes referred to “PPD”) istraditionally expressed as a cutaneous phototoxic inflammatory responseand/or eruption resulting from exposure to one or more photosensitizing,chemical compounds (e.g., botanical substances) and electromagneticradiation (e.g., ultraviolet (UV) radiation) emanating primarily fromthe sun.

The photosensitizing, chemical compounds or skin toxins that result inhuman phytophotodermatitis are traditionally produced by members ofseveral plant families including, but not limited to, Umbelliferae,Leguminosae, Apiaceae, Rutaceae, Moraceae, Roasceae, Asteraceae,Brassicaceae, Clusiaceae, Convolvulaceae, Anacardiaceae, Fabaceae, andRanunculaceae. Common plants implicated in these families include, butare not limited to, celery, giant hogweed, angelica, parsnip, fennel,dill, anise, parsley, lime, lemon, rue, fig, mustard, scurf pea, andchrysanthemums—just to name a few. Notably, giant hogweed is soproblematic that the United States Government regulates it as a federalnoxious weed.

Among the skin toxins produced by plants in the above-identified plantfamilies are furanocoumarins including, but not limited to, psoralen,8-isopentenyloxypsoralen (imperatorin), 5-hydroxypsoralen (bergaptol),5-methoxypsoralen (5-MOP), 8-hydroxypsoralen (xanthotoxol),8-methoxypsoralen (8-MOP), 5,8-dihydroxypsoralen, 5,8-dimethoxypsoralen(isopimpinellin), angelicin, and sphondin. Chemical structures ofnon-limiting, representative furanocoumarins are provided below.

It is believed that exposure to electromagnetic radiation, such as UV-Alight enables furanocoumarins to absorb energy, thereby alteringreactivity of their molecular structures, as well as attain activated,high-energy states. In the presence of oxygen, activated molecules arebelieved to form photoaddition products with DNA pyrimidine bases viaDNA interstrand crosslinking at cytosine and thymidine with the furanring of the furanocoumarins, which results in epidermal cell nucleicdamage. In the absence of oxygen, activated furanocoumarins are alsobelieved to produce oxygen, superoxides, and hydroxy radicals, which arebelieved cause cellular membrane damage.

Responses and/or eruptions from PPD typically begin approximately 24hours after exposure and peak between approximately 48 hours andapproximately 72 hours after exposure. Phytophotodermatitis normallymanifests as a burning erythema that is often followed by blistering,epidermal necrosis, and/or desquamation. Postinflammatoryhyperpigmentation lasting weeks to several months typically follows theacute response and/or eruption from PPD. Affected areas often remainhypersensitive to UV radiation for many years and re-eruptions oflesions and blisters is common.

Until now, the only known antidote for contact with and/or exposure tothese skin toxins was to immediately wash the skin thoroughly with soapand water, thereby removing at least some of the toxins and hopefullyminimizing any reaction with subsequent exposure to sunlight.Unfortunately, the average victim is usually not aware of exposure tothe photosensitizing, chemical compounds until a response and/oreruption occurs and problematic symptoms begin to manifest. Once thishas occurred, washing with soap and water is ineffective and potentiallycontraindicated for certain reactions—likely because the plant toxinshave penetrated into the epidermis and/or dermis. Currently, it isrecommended that once problematic symptoms begin to manifest,professional medical advice should be sought immediately because medicaltreatment with prescription topical steroids may reduce the severity ofa person's reaction. It is further currently recommended to cover anyburns and blisters with sterile dressings to prevent infection, and towear clothing that shields the skin from sunlight. Long-term, use of sunblock in subsequent years and the wearing of sun protective clothing maybe required to prevent sensitization by sunlight.

While the above-identified medical treatments do appear to provide atleast some relief to those who are afflicted by phytophotodermatitis,such treatment remains non-desirous and/or problematic inasmuch as,among other things, none of the above-identified treatments providesufficient therapeutic relief from the debilitating effects of PPD.

It is therefore an object of the present invention to provide a methodfor treating phytophotodermatitis which offers timely relief from thesymptoms presented when one is afflicted with PPD.

These and other objects of the present invention will become apparent inlight of the present specification, claims, and drawings.

SUMMARY OF THE INVENTION

In one embodiment, the present invention is directed to a method fortreating phytophotodermatitis comprising the step of: applying anisothiocyanate functional surfactant to an area affected byphytophotodermatitis, wherein said isothiocyanate functional surfactantcomprises at least one isothiocyanate functional group associated withan aliphatic and/or aromatic carbon atom of the isothiocyanatefunctional surfactant.

In another embodiment of the present invention, the method for treatingphytophotodermatitis further comprises the step of removing theisothiocyanate functional surfactant from the area affected byphytophotodermatitis.

In yet another exemplary embodiment, the present invention is directedto a method for treating phytophotodermatitis comprising the steps of:(a) applying an isothiocyanate functional surfactant to an area affectedby phytophotodermatitis, wherein said isothiocyanate functionalsurfactant comprises at least one isothiocyanate functional groupassociated with an aliphatic and/or aromatic carbon atom of theisothiocyanate functional surfactant; (b) removing the isothiocyanatefunctional surfactant from the area affected by phytophotodermatitis;and (c) repeating the steps of applying and removing the isothiocyanatefunctional surfactant to/from the affected area.

The present invention is also directed to a method for treatingphytophotodermatitis comprising the step of: washing an area affected byphytophotodermatitis with an isothiocyanate functional surfactant,wherein said isothiocyanate functional surfactant comprises at least oneisothiocyanate functional group associated with an aliphatic and/oraromatic carbon atom of the isothiocyanate functional surfactant.

The present invention is further directed to a method for treatingphytophotodermatitis comprising the step of: applying a lysinederivative to an area affected by phytophotodermatitis, wherein thelysine derivative comprises an α-nitrogen and a ε-nitrogen, and whereinan alkyl and/or alkanoyl substituent comprising at least approximately 8carbon atoms is associated with the α-nitrogen, and further wherein atleast one isothiocyanate functional group is associated with theε-nitrogen.

The present invention is still further directed to a method for treatingphytophotodermatitis comprising the step of: applying a surfactant to anarea affected by phytophotodermatitis, wherein the protonated form ofsaid surfactant is represented by the following chemical structure:

wherein the surfactant comprises a non-polar moiety (NP) and a polarmoiety (P), and wherein at least one isothiocyanate functional group(NCS) is associated with the polar and/or non-polar moiety.

In another embodiment, the present invention is directed to a method fortreating phytophotodermatitis, comprising the step of: applying asurfactant or a pharmaceutically acceptable salt thereof to an areaaffected by phytophotodermatitis, wherein the protonated form of saidsurfactant is represented by the following chemical structure:

wherein R₁ comprises an alkyl, cycloalkyl, polycycloalkyl,heterocycloalkyl, aryl, alkaryl, aralkyl, alkoxy, alkanoyl, aroyl,alkenyl, alkynyl and/or cyano group containing approximately 1 toapproximately 25 carbon atom(s), wherein the carbon atom(s) may be alinking group to, or part of, a halogen, a N, O, and/or S containingmoiety, and/or one or more functional groups comprising alcohols,esters, ammonium salts, phosphonium salts, and combinations thereof; alinkage to a dimer; a linkage to an oligomer; and/or a linkage to apolymer; wherein R₂ comprises NCS; and wherein R₃-R₅ are the same ordifferent and comprise H; OH; an alkyl, cycloalkyl, polycycloalkyl,heterocycloalkyl, aryl, alkaryl, aralkyl, alkoxy, alkanoyl, aroyl,alkenyl, alkynyl and/or cyano group containing approximately 1 toapproximately 25 carbon atom(s), wherein the carbon atom(s) may be alinking group to, or part of, a halogen, a N, O, and/or S containingmoiety, and/or one or more functional groups comprising alcohols,esters, ammonium salts, phosphonium salts, and combinations thereof; alinkage to a dimer; a linkage to an oligomer; and/or a linkage to apolymer with the proviso that at least one of R₃-R₅ comprise an alkyl,cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl, aralkyl,alkoxy, alkanoyl, aroyl, alkenyl, alkynyl and/or cyano group containingapproximately 8 to approximately 25 carbon atom(s).

The present invention is also directed to a method for treatingphytophotodermatitis comprising the step of: applying a surfactant or apharmaceutically acceptable salt thereof to an area affected byphytophotodermatitis, wherein the protonated form of said surfactant isrepresented by the following chemical structure:

wherein X comprises an integer ranging from approximately 1 toapproximately 25, and wherein Y comprises an integer ranging fromapproximately 6 to approximately 25.

In a preferred embodiment, the present invention is directed to a methodfor treating phytophotodermatitis comprising the step of: applying asurfactant or a pharmaceutically acceptable salt thereof to an areaaffected by phytophotodermatitis, wherein the protonated form of saidsurfactant is represented by the following chemical structure:

In another embodiment, the present invention is directed to a method fortreating phytophotodermatitis, comprising the step of: applying asurfactant or a pharmaceutically acceptable salt thereof to an areaaffected by phytophotodermatitis, wherein the protonated form of saidsurfactant is represented by the following chemical structure:

wherein R₁ comprises an alkyl, cycloalkyl, polycycloalkyl,heterocycloalkyl, aryl, alkaryl, aralkyl, alkoxy, alkanoyl, aroyl,alkenyl, alkynyl and/or cyano group containing approximately 1 toapproximately 25 carbon atom(s), wherein the carbon atom(s) may be alinking group to, or part of, a halogen, a N, O, and/or S containingmoiety, and/or one or more functional groups comprising alcohols,esters, ammonium salts, phosphonium salts, and combinations thereof; alinkage to a dimer; a linkage to an oligomer; and/or a linkage to apolymer; wherein R₂ comprises NCS; wherein R₃-R₅ are the same ordifferent and comprise H; OH; an alkyl, cycloalkyl, polycycloalkyl,heterocycloalkyl, aryl, alkaryl, aralkyl, alkoxy, alkanoyl, aroyl,alkenyl, alkynyl and/or cyano group containing approximately 1 toapproximately 25 carbon atom(s), wherein the carbon atom(s) may be alinking group to, or part of, a halogen, a N, O, and/or S containingmoiety, and/or one or more functional groups comprising alcohols,esters, ammonium salts, phosphonium salts, and combinations thereof; alinkage to a dimer; a linkage to an oligomer; and/or a linkage to apolymer with the proviso that at least one of R₃-R₅ comprise an alkyl,cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl, aralkyl,alkoxy, alkanoyl, aroyl, alkenyl, alkynyl and/or cyano group containingapproximately 8 to approximately 25 carbon atom(s), wherein X comprisesa counter cation such as, but not limited to, alkali metals, alkalineearth metals, transition metals, s-block metals, d-block metals, p-blockmetals, NZ₄ ⁺, wherein Z comprises, H, R₆, OR₆, and wherein R₆ comprisesan alkyl, cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl,aralkyl, alkoxy, alkanoyl, aroyl, alkenyl, alkynyl and/or cyano groupcontaining approximately 1 to approximately 25 carbon atom(s), whereinthe carbon atom(s) may be a linking group to, or part of, a halogen, aN, O, and/or S containing moiety, and/or one or more functional groupscomprising alcohols, esters, ammonium salts, phosphonium salts, andcombinations thereof; a linkage to a dimer; a linkage to an oligomer;and/or a linkage to a polymer.

In yet another preferred embodiment, the present invention is directedto a method for treating phytophotodermatitis as disclosed supra,further comprising the step of applying an additional surfactant,wherein the additional surfactant is selected from at least one of thegroup comprising a non-ionic surfactant, an anionic surfactant, acationic surfactant, a zwitterionic surfactant, and combinationsthereof.

DETAILED DESCRIPTION OF THE INVENTION

While this invention is susceptible of embodiment in many differentforms, there is shown in the drawings and described herein in detailseveral specific embodiments with the understanding that the presentdisclosure is to be considered as an exemplification of the principlesof the invention and is not intended to limit the invention to theembodiments illustrated.

In accordance with the present invention, methods for treatingphytophotodermatitis are provided herein. In particular, methods fortreating phytophotodermatitis preferably caused by exposure to linearand/or non-linear (e.g., angular) furanocoumarins and derivativesthereof are disclosed. Non-limiting examples of linear furanocoumarinsinclude psoralen, 8-isopentenyloxypsoralen (imperatorin),5-hydroxypsoralen (bergaptol), 5-methoxypsoralen (5-MOP),8-hydroxypsoralen (xanthotoxol), 8-methoxypsoralen (8-MOP),5,8-dihydroxypsoralen, and 5,8-dimethoxypsoralen (isopimpinellin).Non-limiting examples of angular furanocoumarins include angelicin andsphondin. As briefly discussed supra, the photosensitizing, chemicalcompounds and/or skin toxins that result in phytophotodermatitis aretraditionally produced by members of several plant families including,but not limited to, Umbelliferae, Leguminosae, Apiaceae, Rutaceae,Moraceae, Roasceae, Asteraceae, Brassicaceae, Clusiaceae,Convolvulaceae, Anacardiaceae, Fabaceae, and Ranunculaceae. Indeed,common plants implicated in these families include, but are not limitedto, celery, giant hogweed, angelica, parsnip, fennel, dill, anise,parsley, lime, lemon, rue, fig, mustard, scurf pea, andchrysanthemums—just to name a few. It will be understood thatphytophotodermatitis caused by exposure to giant hogweed (i.e.,Heracleum mantegazzianum) is particularly problematic in the UnitedStates. While methods for treating phytophotodermatitis caused byexposure to linear and/or non-linear (e.g., angular) furanocoumarins aredisclosed in detail herein, it will be understood that methods fortreating phytophotodermatitis caused by exposure to otherphotosensitizing, chemical compounds are likewise contemplated for usein accordance with the present invention.

In one embodiment, the present invention is directed to a method fortreating phytophotodermatitis comprising the steps of applying one ormore isothiocyanate functional surfactants to an area affected byphytophotodermatitis. Preferably, the isothiocyanate functionalsurfactant comprises one or more isothiocyanate functional groupsassociated with and/or directly associated with an aliphatic and/oraromatic carbon atom of the isothiocyanate functional surfactant. Itwill be understood that an area affected by phytophotodermatitis maycomprise areas proximate and/or contiguous to areas where amanifestation of physical symptoms are present. Physical symptomsinclude, for example, discomfort, itching, burning, erythema,blistering, epidermal necrosis, desquamation, discoloration, and/orhyperpigmentation—just to name a few. It will be further understood thatisothiocyanate functional surfactants, regardless of their ordinarymeaning, are defined herein as a surfactant having an isothiocyanatefunctional group associated therewith. It will be yet further understoodthat the term associated as applied to chemical contexts, regardless ofits ordinary meaning, is defined herein as attached, a covalent bond, apolar covalent bond, an ionic bond, a hydrogen bond, van der Waalsforces, electrostatic interaction, etcetera.

The term surfactant derives from contraction of the termssurface-active-agent and is defined herein as a molecule and/or group ofmolecules which are able to modify the interfacial properties of theliquids (aqueous and non-aqueous) in which they are present. Thesurfactant properties of these molecules reside in their amphiphiliccharacter which stems from the fact that each surfactant molecule hasboth a hydrophilic moiety and a hydrophobic (or lipophilic) moiety, andthat the extent of each of these moieties is balanced so that atconcentrations at or below the critical micelle concentration (i.e.,CMC) they generally concentrate at the air-liquid interface andmaterially decrease the interfacial tension. For example, sodium saltsof saturated carboxylic acids are extremely soluble in water up to C8length and are thus not true surfactants. They become less soluble inwater from C9 up to C18 length, the domain of effective surfactants forthis class of compounds. The carboxylic acids (fatty acids) can beeither saturated or unsaturated starting from C16 chain lengths.

Without being bound by any one particular theory, it is believed thatthe isothiocyanate functional surfactants disclosed herein facilitatetreatment of numerous forms of phytophotodermatitis by boosting thebody's immune system. It is also believed that the isothiocyanatefunctional surfactants disclosed herein facilitate elevating phase IIenzymes (e.g., HAD(P)H quinine oxidoreductase) which are believed to,among other things regulate inflammatory responses within the body, aswell as detoxify carcinogens and activated carcinogens.

In accordance with the present invention, the isothiocyanate functionalsurfactants may be used as a topical leave-on product in which one ormore surfactants remain on the skin and are not immediately and/or everrinsed off away from the skin. Alternatively, the isothiocyanatefunctional surfactants of the present invention may be used as a topicalwash in an apply-and-rinse fashion. For either case, it is preferredthat the isothiocyanate functional surfactants be generally mild tohuman skin (e.g., non-irritating or low-irritating). In particular,anionic N-alkanoyl surfactants derived from amino acids are especiallypreferred because, while not completely predictable, they have atendency to be mild. The methods of preparation detailed in thisinvention employ but are not limited to amino acids that possess atleast two amine functionalities, at least one of which is converted toan N-alkanoyl functionality, and at least one of which is converted intoisothiocyanate functionality. The amino acids include but are notlimited to the α-amino acids lysine, ornithine, 2,4-diaminobutanoicacid, 2,3-diaminopropionic acid, 2,7-diaminoheptanoic acid, and2,8-diaminooctanoic acid. Additionally, amino acids other than α-aminoacids may be employed, such as β-amino acids, etcetera. It will beunderstood that amino acid derived surfactants are preferred due totheir mild nature, but any one of a number of other surfactants arelikewise contemplated for use in accordance with the present invention.

Method for preparing isothiocyanate functional surfactants and/or theirprecursors can involve but is not limited to conversion of an aminefunctionality to an isothiocyanate functionality. The method ofconversion of amine functionalities to isothiocyanate functionalitiescan be, but is not limited to: (1) reaction with carbon disulfide toyield an intermediate dithiocarbamate, followed by reaction withethylchloroformate or its functional equivalent such asbis(trichloromethyl)-carbonate, trichloromethyl chloroformate, orphosgene; (2) reaction with thiophosgene; (3) reaction with1,1′-thiocarbonyldiimidizole; (4) reaction with phenylthiochloroformate;(5) reaction with ammonium or alkali metal thiocyanate to prepare anintermediate thiourea followed by cleaving to the isothiocyanate viaheating; and (6) reaction with an isothiocyanato acyl halide[SCN—(CH₂)_(n)—CO—Cl]. The resulting isothiocyanate functionalsurfactant, depending on the method of preparation, can be isolated as apure material or as a mixture with other surfactants. The resultingisothiocyanate functional surfactant, depending on the method ofpreparation, can be isolated and used directly in nonionic form, anionicform, cationic form, zwitterionic (amphoteric) form, or in a neutralsurfactant-precursor form in combination with a base such as sodiumhydroxide or triethanol amine if the neutral surfactant-precursor formpossesses a protonated carboxylic acid group such that reaction(deprotonation) with the base converts the neutral surfactant-precursorform to an anionic surfactant, or in neutral surfactant-precursor formin combination with an acid if the neutral surfactant-precursor formpossess amine functionality such that reaction (protonation) with theacid converts the neutral surfactant-precursor form to a cationicsurfactant.

In accordance with the present invention the step of applying comprises,but is not limited to, spraying, dripping, dabbing, rubbing, blotting,dipping, and any combination thereof.

In a preferred embodiment of the present invention, the isothiocyanatefunctional surfactant is removed from the affected area after a periodof time. Such a period comprises, but is not limited to, seconds (e.g.,1 second, 2 seconds, 5 seconds, 10 seconds, 15 seconds, 20 seconds, 30seconds, 45 seconds, and 60 seconds), minutes (e.g. 1 minutes, 2minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45minutes, and 60 minutes), hours (e.g. 1 hour, 2 hours, 5 hours, 10hours, 15 hours, 20 hours, 30 hours, 45 hours, and 60 hours), days (e.g.1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days,21 days, 30 days), etcetera. It will be understood that the step ofremoving preferably occurs via rinsing, wiping, and/or extracting—justto name a few.

Depending upon the subject and/or the severity of thephytophotodermatitis, multiple applications may be necessary. As such,the steps of applying and/or removing the isothiocyanate functionalsurfactant may be repeated one or a plurality of times.

The present invention is also directed to a method for treatingphytophotodermatitis comprising the steps of applying a lysinederivative to an area affected by phytophotodermatitis, wherein thelysine derivative comprises an α-nitrogen and a ε-nitrogen. Preferably,an alkyl substituent comprising at least approximately 8 carbon atoms isassociated with the α-nitrogen. Preferably, at least one isothiocyanatefunctional group is associated with the ε-nitrogen.

The present invention is further directed to a method for treatingphytophotodermatitis comprising the steps of: applying a surfactant toan area affected by phytophotodermatitis, wherein the surfactant isrepresented by the following chemical structure:

and wherein the surfactant comprises a non-polar moiety (NP) and a polarmoiety (P), and wherein at least one isothiocyanate functional group(NCS) is associated with the polar and/or non-polar moiety.

The present invention is yet further directed to a method for treatingphytophotodermatitis, comprising the step of: applying a surfactant or apharmaceutically acceptable salt thereof to an area affected byphytophotodermatitis, wherein the protonated form of said surfactant isrepresented by the following chemical structure:

wherein R₁ comprises an alkyl, cycloalkyl, polycycloalkyl,heterocycloalkyl, aryl, alkaryl, aralkyl, alkoxy, alkanoyl, aroyl,alkenyl, alkynyl and/or cyano group containing approximately 1 toapproximately 25 carbon atom(s), wherein the carbon atom(s) may be alinking group to, or part of, a halogen, a N, O, and/or S containingmoiety, and/or one or more functional groups comprising alcohols,esters, ammonium salts, phosphonium salts, and combinations thereof; alinkage to a dimer; a linkage to an oligomer; and/or a linkage to apolymer; wherein R₂ comprises NCS; and wherein R₃-R₅ are the same ordifferent and comprise H; OH; an alkyl, cycloalkyl, polycycloalkyl,heterocycloalkyl, aryl, alkaryl, aralkyl, alkoxy, alkanoyl, aroyl,alkenyl, alkynyl and/or cyano group containing approximately 1 toapproximately 25 carbon atom(s), wherein the carbon atom(s) may be alinking group to, or part of, a halogen, a N, O, and/or S containingmoiety, and/or one or more functional groups comprising alcohols,esters, ammonium salts, phosphonium salts, and combinations thereof; alinkage to a dimer; a linkage to an oligomer; and/or a linkage to apolymer with the proviso that at least one of R₃-R₅ comprise an alkyl,cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl, aralkyl,alkoxy, alkanoyl, aroyl, alkenyl, alkynyl and/or cyano group containingapproximately 8 to approximately 25 carbon atom(s).

In this embodiment, the surfactant is preferably represented by thefollowing chemical structure:

wherein X comprises an integer ranging from approximately 1 toapproximately 25, and wherein Y comprises an integer ranging fromapproximately 6 to approximately 25.

More preferably, the surfactant is represented by the following chemicalstructure:

In another embodiment, the present invention is directed to a method fortreating phytophotodermatitis, comprising the step of: applying asurfactant or a pharmaceutically acceptable salt thereof to an areaaffected by phytophotodermatitis, wherein the protonated form of saidsurfactant is represented by the following chemical structure:

wherein R₁ comprises an alkyl, cycloalkyl, polycycloalkyl,heterocycloalkyl, aryl, alkaryl, aralkyl, alkoxy, alkanoyl, aroyl,alkenyl, alkynyl and/or cyano group containing approximately 1 toapproximately 25 carbon atom(s), wherein the carbon atom(s) may be alinking group to, or part of, a halogen, a N, O, and/or S containingmoiety, and/or one or more functional groups comprising alcohols,esters, ammonium salts, phosphonium salts, and combinations thereof; alinkage to a dimer; a linkage to an oligomer; and/or a linkage to apolymer; wherein R₂ comprises NCS; wherein R₃-R₅ are the same ordifferent and comprise H; OH; an alkyl, cycloalkyl, polycycloalkyl,heterocycloalkyl, aryl, alkaryl, aralkyl, alkoxy, alkanoyl, aroyl,alkenyl, alkynyl and/or cyano group containing approximately 1 toapproximately 25 carbon atom(s), wherein the carbon atom(s) may be alinking group to, or part of, a halogen, a N, O, and/or S containingmoiety, and/or one or more functional groups comprising alcohols,esters, ammonium salts, phosphonium salts, and combinations thereof; alinkage to a dimer; a linkage to an oligomer; and/or a linkage to apolymer with the proviso that at least one of R₃-R₅ comprise an alkyl,cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl, aralkyl,alkoxy, alkanoyl, aroyl, alkenyl, alkynyl and/or cyano group containingapproximately 8 to approximately 25 carbon atom(s), wherein X comprisesa counter cation such as, but not limited to, alkali metals, alkalineearth metals, transition metals, s-block metals, d-block metals, p-blockmetals, NZ₄ ⁺, wherein Z comprises, H, R₆, OR₆, and wherein R₆ comprisesan alkyl, cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl,aralkyl, alkoxy, alkanoyl, aroyl, alkenyl, alkynyl and/or cyano groupcontaining approximately 1 to approximately 25 carbon atom(s), whereinthe carbon atom(s) may be a linking group to, or part of, a halogen, aN, O, and/or S containing moiety, and/or one or more functional groupscomprising alcohols, esters, ammonium salts, phosphonium salts, andcombinations thereof; a linkage to a dimer; a linkage to an oligomer;and/or a linkage to a polymer.

In accordance with the present invention, the isothiocyanate functionalsurfactant may also be associated with an additional surfactant, whereinthe additional surfactant is selected from at least one of the groupcomprising a non-ionic surfactant, an anionic surfactant, a cationicsurfactant, a zwitterionic surfactant, and combinations thereof.

Non-limiting examples of preferred anionic surfactants include taurates;isethionates; alkyl and alkyl ether sulfates; succinamates; alkylsulfonates, alkylaryl sulfonates; olefin sulfonates; alkoxy alkanesulfonates; sodium and potassium salts of fatty acids derived fromnatural plant or animal sources or synthetically prepared; sodium,potassium, ammonium, and alkylated ammonium salts of alkylated andacylated amino acids and peptides; alkylated sulfoacetates; alkylatedsulfosuccinates; acylglyceride sulfonates, alkoxyether sulfonates;phosphoric acid esters; phospholipids; and combinations thereof.Specific anionic surfactants contemplated for use include, but are by nomeans limited to, ammonium cocoyl isethionate, sodium cocoylisethionate, sodium lauroyl isethionate, sodium stearoyl isethionate,sodium lauroyl sarcosinate, sodium cocoyl sarcosinate, sodium laurylsarcosinate, disodium laureth sulfosuccinate, sodium laurylsulfoacetate, sodium cocoyl glutamate, TEA-cocoyl glutamate, TEA cocoylalaninate, sodium cocoyl taurate, potassium cetyl phosphate.

Non-limiting examples of preferred cationic surfactants includealkylated quaternary ammonium salts R₄NX; alkylated amino-amides(RCONH—(CH₂)_(n))NR₃X; alkylimidazolines; alkoxylated amines; andcombinations thereof. Specific examples of anionic surfactantscontemplated for use include, but are by no means limited to, cetylammonium chloride, cetyl ammonium bromide, lauryl ammonium chloride,lauryl ammonium bromide, stearyl ammonium chloride, stearyl ammoniumbromide, cetyl dimethyl ammonium chloride, cetyl dimethyl ammoniumbromide, lauryl dimethyl ammonium chloride, lauryl dimethyl ammoniumbromide, stearyl dimethyl ammonium chloride, stearyl dimethyl ammoniumbromide, cetyl trimethyl ammonium chloride, cetyl trimethyl ammoniumbromide, lauryl trimethyl ammonium chloride, lauryl trimethyl ammoniumbromide, stearyl trimethyl ammonium chloride, stearyl trimethyl ammoniumbromide, lauryl dimethyl ammonium chloride, stearyl dimethyl cetylditallow dimethyl ammonium chloride, dicetyl ammonium chloride, dilaurylammonium chloride, dilauryl ammonium bromide, distearyl ammoniumchloride, distearyl ammonium bromide, dicetyl methyl ammonium chloride,dicetyl methyl ammonium bromide, dilauryl methyl ammonium chloride,distearyl methyl ammonium chloride, distearyl methyl ammonium bromide,ditallow dimethyl ammonium chloride, ditallow dimethyl ammonium sulfate,di(hydrogenated tallow) dimethyl ammonium chloride, di(hydrogenatedtallow) dimethyl ammonium acetate, ditallow dipropyl ammonium phosphate,ditallow dimethyl ammonium nitrate, di(coconutalkyl)dimethyl ammoniumchloride, di(coconutalkyl)dimethyl ammonium bromide, tallow ammoniumchloride, coconut ammonium chloride, stearamidopropyl PG-imoniumchloride phosphate, stearamidopropyl ethyldimonium ethosulfate,stearimidopropyldimethyl (myristyl acetate) ammonium chloride,stearamidopropyl dimethyl cetearyl ammonium tosylate, stearamidopropyldimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate,ditallowyl oxyethyl dimethyl ammonium chloride, behenamidopropyl PGdimonium chloride, dilauryl dimethyl ammonium chloride, distearlydimethyl ammonium chloride, dimyristyl dimethyl ammonium chloride,dipalmityl dimethyl ammonium chloride, distearyl dimethyl ammoniumchloride, stearamidoproyl PG-dimonium chloride phosphate,stearamidopropyl ethyldiammonium ethosulfate, stearamidopropyl dimethyl(myristyl acetate) ammonium chloride, stearimidopropyl dimethyl diemthylcetaryl ammonium tosylate, stearamido propyl dimethyl ammonium chloride,stearamidopropyl dimethyl ammonium lactate.

Non-limiting examples of preferred non-ionic surfactants includealcohols, alkanolamides, amine oxides, esters (including glycerides,ethoxylated glycerides, polyglyceryl esters, sorbitan esters,carbohydrate esters, ethoxylated carboxylic acids, phosphoric acidtriesters), ethers (including ethoxylated alcohols, alkyl glucosides,ethoxylated polypropylene oxide ethers, alkylated polyethylene oxides,alkylated polypropylene oxides, alkylated PEG/PPO copolymers), siliconecopolyols. Specific examples of non-ionic surfactants contemplated foruse include, but are by no means limited to, cetearyl alcohol,ceteareth-20, nonoxynol-9, C12-15 pareth-9, POE(4) lauryl ether,cocamide DEA, glycol distearate, glyceryl stearate, PEG-100 stearate,sorbitan stearate, PEG-8 laurate, polyglyceryl-10 trilaurate, laurylglucoside, octylphenoxy-polyethoxyethanol, PEG-4 laurate, polyglyceryldiisostearate, polysorbate-60, PEG-200 isostearyl palmitate, sorbitanmonooleate, polysorbate-80.

Non-limiting examples of preferred zwitterionic or amphotericsurfactants include betaines; sultaines; hydroxysultaines, amidobetaines, amidosulfo betaines; and combinations thereof. Specificexamples of amphoteric surfactants contemplated for use include, but areby no means limited to, cocoamidopropyl sultaine, cocoamidopropylhydroxyl sultaine, cocoamidopropylbetaine, coco dimethyl carboxymethylbetaine, lauryl dimethyl carboxymethyl betaine, lauryl dimethylalphacarboxyethyl betaine, cetyl dimethyl carboxymethyl betaine, cetyldimethyl betaine, lauryl (2-bishydroxy) carboxymethyl betaine, stearylbis-(2-hydroxyethyl) carboxymethyl betaine, oelyl dimethylgamma-carboxypropyl betaine, lauryl bis-(2-hydroxypropyl)alphacarboxymethyl betaine, coco dimethyl sulfopropyl betaine, stearyldimethyl sulfopropyl betaine, lauryl dimethyl sulfoethyl betaine, laurylbis(2-hydroxyethyl) sulfopropyl betaine, oleyl betaine, cocamidopropylbetaine.

The invention is further described by the following examples.

Example I Preparation of a Mixture ofN_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysine with N_(α),N_(ε)-bis-lauroyl-L-lysine

A 1 liter beaker equipped with an overhead mechanical stainless steelpaddle stirrer was charged with 100 mL of 1 M NaOH (0.100 mol). Stirringwas begun and the beaker cooled to −5° C. to −10° C. using a salt/icebath. Next, 23.4 g (0.100 mol) of N_(ε)-benzylidene-L-lysine (preparedvia the method of Bezas, B and Zervas, L., JACS, 83, 1961, 719-722) wasadded. Immediately afterward and while keeping the solution cold, 140 mL(0.140 mol) of precooled (in a salt/ice bath) 1 M NaOH and 26.1 mL oflauroyl chloride was added in two equal portions over a period of 6minutes. The mixture was stirred for 10 more minutes at −5 to −10° C.,then the ice bath was removed and the reaction mixture allowed to stirfor another 1 hour while warming to room temperature. Next, the reactionmixture was cooled using a salt/ice bath and then sufficientconcentrated HCl was added to adjust the pH to 7.5-7.8. With the pH at7.8-7.8 and with continued cooling and stirring, 4.6 mL (60% ofstoichiometric, 0.068 mol) of thiophosgene was added drop-wise via anadditional funnel over the period of 1 hour. During this time,sufficient 1 M NaOH was added to maintain a pH range between 7.5-7.8.After the thiophosgene addition was complete, additional 1 M NaOH wasadded as necessary until the pH stabilized in 7.5-7.8 range. Next,sufficient 30% NaOH was added to adjust the pH to approximately 8.5.Next, 12 mL (0.051 mol) of lauroyl chloride was rapidly added, followedby sufficient 1 M NaOH to keep the pH in the range of 8.00-8.50. Next,sufficient concentrated HCl was added to adjust the pH to 1.5. Thereaction mixture was filtered via vacuum filtration, and the precipitatewashed with dilute HCl (pH=2). The product, a white moist solid, wasdried in vacuo while heating to 60° C. 45.19 g of white solid productwas recovered, a mixture of predominantlyN_(α)-lauroyl-N_(ε)-isothiocyanato-L-lysine andN_(α),N_(ε)-bis-lauroyl-L-lysine (determined via LC-MS analysis). Bothcompounds in this mixture can be simultaneously converted into anionic(carboxylate) surfactants via reaction with aqueous NaOH to yield aclear aqueous solution of the surfactants.

Example II Preparation of PureN_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysine Step 1: Preparation ofN_(α)-lauroyl-N_(ε)-carbobenzoxy-L-Lysine

60.0 g of N_(ε)-cbz-L-Lysine (cbz is carbobenzoxy) purchased fromAtomole Scientific Company, LTD was added to a three-liter beaker alongwith 1200 mL of RO water and the mixture was stirred. Next, 39 mL of 30%aqueous NaOH was added, resulting in dissolution of theN_(ε)-cbz-L-Lysine. The resulting solution was cooled in an ice bath andthen 52.5 mL of lauroyl chloride was added. The ice bath was removed 30minutes later, and stirring continued for an additional six hours, atwhich time 18 mL of concentrated hydrochloric acid was added. Thereaction mixture was then filtered via vacuum filtration, the whitesolid product washed with 1 M aqueous HCl, and then the solid productwas dried in vacuo while heated to approximately 85° C. 96.5 g of drywhite solid product was obtained. The product can be further purified bydissolving it in methanol, filtering off any insoluble precipitate, andremoving the methanol in vacuo to recover a white solid product (mp99.5-103.0° C.)

Step 2: Preparation of N_(α)-lauroyl-N_(ε)-ammonium chloride-L-Lysine

10.0 g of N_(α)-lauroyl-N_(ε)-carbobenzoxy-L-Lysine was weighed into aone liter Erlenmeyer flask equipped with a magnetic stir bar. 150 mL ofconcentrated hydrochloric acid was added and the solution was stirredand heated in an oil bath to 104° C., then allowed to cool with the oilbath back to room temperature. The solution was then cooled to 9° C. forapproximately four hours, during which time a large mass of whiteprecipitate formed. The reaction mixture was filtered in vacuo andrinsed with a small amount of cold 1 M HCl. The white solid reactionproduct was then dried in vacuo while being heated to 78° C., yielding7.89 g of white solid product (mp 191-193° C.).

Step 3: Preparation of N_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysine

0.46 mL of thiophosgene was added to 30 mL of dichloromethane in a 125mL Erlenmeyer flask equipped with a magnetic stir bar. To this solutionwas drop wise added over 15 minutes a solution consisting of 2.00 gN_(α)-lauroyl-N_(ε)-ammonium chloride-L-Lysine, 10 mL RO water, and 2.7mL 20% aqueous NaOH. Stirring was continued for an additional 30minutes, after which sufficient concentrated hydrochloric acid was addedto lower the pH to 1 as indicated by testing with pHydrion paper. Thereaction solution was then transferred into a separatory funnel and thebottom turbid dichloromethane layer was isolated and dried withanhydrous magnesium sulfate and gravity filtered. To the filtrate wasadded 50 mL of hexanes. The solution was then concentrated via removalof 34 mL of solvent via trap-to-trap distillation and then placed in a−19° C. freezer. A mass of white precipitate formed after a few hoursand was isolated via vacuum filtration and then dried in vacuo for 2hours. 1.130 g of a slightly off white solid powder product was obtained[mp 37.0-39.0° C.; IR (cm⁻¹), 3301sb, 2923s, 2852s, 2184m, 2099s, 1721s,1650s, 1531s, 1456m, 1416w, 1347m, 1216m, 1136w]

Example III Preparation of a Two-Part Formulation for the Treatment ofPhytophotodermatitis

A two-part formulation for topical application to the skin was preparedas follows:

Part I: A 25% by mass mixture ofN_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysine in Dow Corning DC344 fluid(a mixture of octamethyl-cyclotetrasiloxane anddecamethyl-cyclopentasiloxane) was prepared in a mortar and pestle toproduce a paste that was loaded into a 5 ml plastic disposable syringe.A syringe needle was not employed. Rather, the dispensing end of thesyringe was capped except for when dispensing without a syringe needleinto the palm of a hand occurred.

Part II: Part II consisted of Cetaphil Moisturizing Lotion to whichadditional triethanol amine (TEA) was added such that the concentrationof the additional triethanol amine was 0.006 g triethanol amine per gramof lotion, raising the pH of the Cetaphil Lotion from 7.74 to 8.77.

Preferred Instructions for Application of Formulation to the Skin: A 0.2mL portion of the N_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysine/DC344mixture is dispensed from the syringe into the palm of a hand(approximately 0.13 g of the mixture). Next, two full squirts of theCetaphil/TEA lotion is dispensed on top of theN_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysine/DC344 mixture (approximately2.8 g of the lotion). Next, using the index finger of the other hand,the components are mixed thoroughly for 30 seconds, during which timethe water insoluble N_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysinesurfactant-precursor is deprotonated to yield the water-soluble anionic(carboxylate) surfactant and yield a homogenous smooth white lotion(this reduces the pH to 7.4). This mixture is then applied to theafflicted areas by gently rubbing it on as one would apply anymoisturizing lotion. Treatment is recommended two to three times per dayuntil the symptoms of the phytophotodermatitis subside.

Example IV Preparation of a One-Part Formulation for the Treatment ofPhytophotodermatitis

A one-part formulation for topical application to the skin was preparedas follows:

First, 0.00025% (by wt.; 5.0 micromolar) of SodiumN_(α)-lauroyl-N_(ε)-isothiocyanate-L-Lysinate, the sodium salt of thematerial provided in step three of Example II, was mixed with 2% LaurylPEG-10 Methyl Ether Dimethicone (commercially available from ClearChemical Corporation, Holland, Mich.) which was QS to achieve 100% with2,6,10,15,19,23-Hexamethyltetracosane (commercially available fromSigma-Aldrich). It will be understood that the concentration of SodiumN_(α)-lauroyl-N_(ε)-isothiocyanate-L-Lysinate may range fromapproximately 0.000001% to approximately 50%. Non-limiting examples ofadditional concentrations include 0.0005%, 0.005%, 0.005%, 0.005%,0.05%, 0.5%, 5% —just to name a few. It will be further understood thatthe concentration of Lauryl PEG-10 Methyl Ether Dimethicone may rangefrom approximately 0.000001% to approximately 50%.

Preferred Instructions for Application of the One-Part Formulation tothe Skin: A 0.1-1.0 mL portion of the one-part formulation is dispensedfrom a container into the palm of a hand for subsequent administrationto an affected area and/or is dispensed directly onto an affected areaby gently rubbing it on as one would apply a moisturizing lotion.Treatment is recommended one to four times per day until the symptoms ofthe phytophotodermatitis subside.

The foregoing description merely explains and illustrates the inventionand the invention is not limited thereto except insofar as the appendedclaims are so limited, as those skilled in the art who have thedisclosure before them will be able to make modifications withoutdeparting from the scope of the invention.

What is claimed and desired to be secured by Letters Patent of theUnited States is:
 1. An isothiocyanate functional surfactantformulation, comprising: a surfactant or a pharmaceutically acceptablesalt thereof, wherein the protonated form of said surfactant isrepresented by the following chemical structure:

wherein R₁ is selected from the group consisting of an alkyl groupcontaining 1 to 25 carbon atom(s); wherein R₂ is selected from the groupconsisting of NCS; and wherein R₃-R₅ are each independently selectedfrom the group consisting of H; OH; and an alkyl, and alkanoyl groupcontaining 1 to 25 carbon atom(s) with the proviso that at least one ofR₃-R₅ is selected from the group consisting of an alkyl, and alkanoyl,group containing 8 to 25 carbon atoms; and2,6,10,15,19,23-hexamethyltetracosane.
 2. The isothiocyanate functionalsurfactant formulation according to claim 1, wherein the concentrationof the isothiocyanate functional surfactant ranges from 0.00025% byweight to 0.0005% by weight.
 3. An isothiocyanate functional surfactantformulation, comprising: a surfactant or a pharmaceutically acceptablesalt thereof, wherein the protonated form of said surfactant isrepresented by the following chemical structure:

wherein X comprises an integer ranging from 1 to 25, and wherein Ycomprises an integer ranging from 6 to 25; and2,6,10,15,19,23-hexamethyltetracosane.
 4. The isothiocyanate functionalsurfactant formulation according to claim 3, wherein the concentrationof the isothiocyanate functional surfactant ranges from 0.00025% byweight to 0.0005% by weight.
 5. An isothiocyanate functional surfactantformulation, comprising: a surfactant or a pharmaceutically acceptablesalt thereof, wherein the protonated form of said surfactant isrepresented by the following chemical structure:

and 2,6,10,15,19,23-hexamethyltetracosane.
 6. The isothiocyanatefunctional surfactant formulation according to claim 5, wherein theconcentration of the isothiocyanate functional surfactant ranges from0.00025% by weight to 0.0005% by weight.